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QSAR Studies on Bacterial Efux Pump Inhibitors
network methods which can deal with non-linear structure-activity relationships. These approaches may
pave the way for the establishment of rapid in silico screening that are routinely applied in the early drug
discovery phase. Additionally, pharmacophore modeling should also be considered in such the cases
where the database includes a large number of compounds that have diverse structural properties. This
method may be used alongside 3D-QSAR in order to assess the drug – transporter interactions, and also to
give certain suggestions on the direction of synthesizing new chemical compounds to inhibit the studied
efflux pumps. The pharmacophore models can be derived from either the binding site of the protein or
a group of active compounds (Guner, 2000; Mannhold, Kubinyi, Folkers, Langer, & Hoffmann, 2006).
Recently, many researchers are working on the efflux pump namely NorA of S. aureus. However, no
X-ray crystal structures have been found until now. Hence, physiological, pharmacological and medicinal
chemistry studies on NorA pump have contributed to our understanding of the structure and mechanism
of drug resistance. Further in silico as well as in vitro studies and X-ray crystal structures of certain ef-
flux pumps like NorA have remained attractive targets to scientist working in intelligent designs of new
novel NorA inhibitors as well as other EPIs.
CONCLUDING REMARKS
This review provides a summary of current knowledge about efflux-pump-mediated multidrug resistance and QSAR studies on bacterial EPIs. QSAR modeling results provide useful information for
structural modifications of existing compounds in order to gain more potent compounds in use. The
major benefits derived from developing efficient EPIs will be the ability to reuse various antibiotics
affected by the efflux pumps as well as the control of the emergence and the dissemination of MDR
efflux strains. Until now, the majority of the known inhibitors have been obtained from screening
libraries of synthetic compounds, from purification of natural compounds or chemical modification
of existing molecules.
As far as Gram-positive bacteria are concerned, most of the QSAR studies on bacterial MDR are
dedicated to NorA in S.aureus. Obtained QSAR analyses, coupled with molecular docking studies,
proved that hydrophobicity and hydrogen bondings are essential for NorA inhibitory activity. For
Gram-negative bacterial EPIs, there has been a modest number of QSAR studies conducted. With the
advent of high-resolution crystal structures of efflux pumps of Escherichia coli and Pseudomonas
aeruginosa, it is hoped that consequent increase in the population of identified molecules with high
EPI capacity would foster ligand-based approaches in this area. For general QSAR studies on bacterial EPIs, 2D-QSAR using partial least squares method and molecular field parameters were largely
employed. Therefore, it is suggested that 3D-QSAR and machine learning methods should be taken
into consideration when generating future QSAR models. Also, additional X-ray structures of proteins
will definitely aid in the understanding of the molecular principles underlying the ligand-protein binding mode of bacterial efflux pumps.
To date, none of bacterial EPIs have entered clinical trials yet, the active compounds found with
EPI-potency should still be subjects of deeper examination, including their pharmacokinetic properties and toxicity, as they give a hope for their future therapeutic usage. Moreover, the development
of combination therapy poses additional complexity due to the necessity of precision tailoring of the
pharmacokinetics of both agents to achieve the desired pharmacodynamic effect.
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QSAR Studies on Bacterial Efux Pump Inhibitors
ACKNOWLEDGMENT
This work was supported by the Vietnam’s National Foundation for Science and Technology Development - NAFOSTED (Grant # 106.99-2012.106 to Khac-Minh Thai).
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